#85 - Iñigo San Millán, Ph.D.: Mitochondria, exercise, and metabolic health
Dr. Iñigo San Millán, Asst. Professor at CU School of Medicine, provides a masterclass on mitochondrial function, energy systems, and exercise. He details six training zones, emphasizing Zone 2 for improving metabolic health and mitochondrial efficiency, and discusses its implications for diabetes and cancer.
Deep Dive Analysis
16 Topic Outline
Dr. Iñigo San Millán's Background and Athletic Journey
Understanding Aerobic and Anaerobic Energy Systems
The Role of Lactate as a Fuel and Signaling Molecule
Iñigo's Six Zones of Exercise Training Explained
Zone 2 Training: Physiological Characteristics and Fat Oxidation
Assessing Mitochondrial Function via Lactate and RQ Tests
Comparing Metabolism: Elite Athletes vs. Metabolically Unhealthy Individuals
Muscle Glycogen Storage and the Athlete's Fat Droplet Paradox
Physiological Characteristics of Zone 3, Zone 4, and Lactate Threshold
Fueling Exercise: Dietary Implications and Carbohydrate Intake
Exercise, Insulin Sensitivity, and Lessons from Type 1 Diabetes
The Impact of Metformin on Mitochondrial Function and Lactate
Raising Awareness for 'Double Diabetes'
Dosing Zone 2 Training for Health and Longevity
The Warburg Effect: Lactate's Role in Carcinogenesis
Doping in Cycling and the Trend Towards Altitude Training
8 Key Concepts
Aerobic Metabolism
This refers to energy production where all metabolic demands are met through mitochondrial oxidation, primarily using fatty acids and glucose. It's about generating ATP at a rate slow enough for the mitochondria to keep up, even if lactate is produced in the cytosol.
Anaerobic Metabolism
This occurs when the demand for ATP exceeds the capacity of the mitochondria and even cytosolic production. The body must rely on ATP already stored in the muscles, as seen in maximal sprints, and does not necessarily involve a lack of oxygen.
Lactate as Fuel/Signaling
Lactate is not merely a waste product but a crucial fuel source, preferred by the brain, and a major signaling molecule. It's constantly produced by every cell and utilized by almost every cell, including being oxidized by slow-twitch muscle fiber mitochondria for energy.
Zone 2 Training
This exercise intensity fully stimulates slow-twitch muscle fibers, leading to the highest amount of fat oxidation (FatMax) without recruiting fast-twitch muscle fibers. It's considered the optimal zone for improving mitochondrial function and efficiency.
Respiratory Quotient (RQ/RER)
This is the ratio of carbon dioxide produced to oxygen consumed, indicating the type of fuel being burned. An RQ of 0.7 suggests primary fat oxidation, while an RQ closer to 1.0 indicates a reliance on glucose, even at rest, which can be a red flag for mitochondrial dysfunction.
Metabolic Flexibility
This refers to the body's capacity to efficiently switch between different fuel sources, primarily fat and glucose, depending on energy demands. Individuals with poor metabolic flexibility, such as those with type 2 diabetes, struggle to oxidize fat efficiently.
Athlete's Paradox (Fat Droplet)
Elite athletes and individuals with type 2 diabetes both exhibit intramuscular fat droplets adjacent to mitochondria. In athletes, these droplets are highly active reservoirs for fat oxidation, while in diabetics, they are static and can contribute to insulin resistance and inflammation.
Warburg Effect
This describes the metabolic characteristic of cancer cells, which consume large amounts of glucose and produce high levels of lactate, even in the presence of oxygen. Lactate is proposed to act as a signaling molecule that promotes carcinogenesis by overexpressing oncogenes and cell cycle genes.
9 Questions Answered
Slow-twitch (Type 1) fibers are less forceful but fatigue slowly, designed for sustained aerobic activity and fat oxidation. Fast-twitch (Type 2) fibers generate more force but fatigue quickly, relying more on glucose for faster ATP generation.
Lactate is not a waste product; it is a crucial fuel source for the brain and other tissues, and a significant signaling molecule. It's a mandatory byproduct of glucose utilization and is efficiently utilized by mitochondria in slow-twitch muscle fibers.
The physical discomfort is primarily caused by the buildup of hydrogen ions, which are associated with lactate and also produced from ATP hydrolysis. These hydrogen ions decrease the contractile capacity and force of muscle fibers, leading to fatigue.
Mitochondrial function can be assessed indirectly by measuring the power output at which an individual achieves their maximum fat oxidation (FatMax) and by observing blood lactate levels during exercise. High lactate levels in the blood indicate inefficient lactate clearance by mitochondria.
A high resting RQ (e.g., 0.9 to 1.0 in a fasted state) is a red flag for mitochondrial dysfunction, indicating that the individual is almost exclusively relying on glucose for energy and not efficiently oxidizing fatty acids, even at rest.
Elite athletes possess exceptionally high insulin sensitivity and mitochondrial function, allowing them to efficiently utilize and clear carbohydrates. Their muscles also have a significantly increased capacity for non-insulin-dependent glucose uptake during exercise.
Exercise significantly increases insulin sensitivity and stimulates non-insulin-dependent glucose uptake by translocating GLUT4 transporters to the muscle cell surface. This allows glucose to enter the muscle without requiring insulin, reducing the body's overall insulin demand.
Double diabetes refers to individuals with type 1 diabetes who also develop type 2 diabetes or insulin resistance. This is a growing concern as many type 1 diabetics may be undiagnosed for their co-occurring type 2 diabetes.
While optimal dosing varies, engaging in Zone 2 training two days a week can help maintain mitochondrial function. To significantly improve it, three to five days a week, for about one to one and a half hours per session, is often effective, especially for those with metabolic dysfunction.
24 Actionable Insights
1. Optimize Mitochondrial Function with Zone 2 Training
Engage in Zone 2 exercise, which is the highest intensity where you can still hold a conversation, or where lactate levels are between 1.5-2.0 millimoles. This stimulates slow-twitch muscle fibers to their fullest, maximizes fat oxidation, and significantly improves mitochondrial efficiency and lactate clearance.
2. Train Zone 2 for Metabolic Health
For individuals with pre-type 2 or type 2 diabetes, aim for 1 to 1.5 hours of Zone 2 training, 3-5 days a week, to significantly improve metabolic flexibility and potentially reverse pre-diabetes.
3. Leverage Zone 2 for Glucose Uptake
Consistent Zone 2 training enhances the non-insulin dependent glucose uptake pathway in muscles, allowing cells to take up glucose without relying on insulin. This is particularly beneficial for insulin sensitivity and glucose regulation.
4. Utilize Food and Exercise as Medicine
Recognize that food and exercise are the most potent tools for managing health and preventing disease, often surpassing the efficacy of pharmaceutical interventions.
5. Adopt Sustainable Lifestyle Changes
When implementing diet or exercise programs, prioritize changes that you can realistically maintain for the rest of your life, as unsustainable extremes often lead to eventual abandonment.
6. Identify Zone 2 by Conversation/Lactate
To find your Zone 2, aim for an exercise intensity where you can still comfortably carry on a conversation, or if using a lactate meter, maintain blood lactate levels between 1.5 and 2.0 millimoles. This ensures you are maximizing fat oxidation and stimulating mitochondrial function.
7. Prioritize Mitochondrial Conditioning Over Calories
When exercising for metabolic health and weight loss, focus on “mitochondrial conditioning” through Zone 2 training rather than simply burning calories. Training too hard can lead to burning less fat during exercise.
8. Implement Cool Down for Hyperglycemia
For individuals experiencing post-exercise hyperglycemia, especially those with diabetes, performing a cool-down period can help lower glucose levels and reduce the need for insulin correction.
9. Exercise Immediately After Meals (Type 2)
For individuals with Type 2 diabetes or insulin resistance, exercising immediately after a meal can leverage muscle contraction to facilitate glucose uptake without requiring as much insulin.
10. Monitor Heart Rate for Training Stress
Understand that a given power output (watts) does not always equate to the same physiological stress; monitor heart rate and lactate levels, as they are physiological parameters that reflect the body’s metabolic stress.
11. Assess Resting RQ for Dysfunction
If your fasting resting respiratory quotient (RQ) or respiratory exchange ratio (RER) is consistently 0.9 or higher, it’s a significant red flag for mitochondrial dysfunction, indicating an over-reliance on glucose over fat for fuel at rest.
12. Maintain Function with Consistent Zone 2
To maintain mitochondrial function and fat-burning capacity, incorporate Zone 2 training at least two days a week. Elite athletes in their off-season use this frequency for maintenance.
13. Incorporate Fasting for Metabolic Balance
Consider integrating various fasting protocols (e.g., weekly, monthly, quarterly) into your routine as a tool to maintain metabolic balance and achieve health goals sustainably.
14. Adjust Insulin Dosing for Exercise (Type 1)
Individuals with Type 1 diabetes should work with clinicians to adjust insulin doses, often reducing them before exercise, to prevent hypoglycemia due to increased insulin sensitivity.
15. Re-evaluate Metformin Use with Zone 2
If you are metabolically healthy and taking metformin, consider experimenting with reducing or timing your dose away from Zone 2 exercise, as it may blunt the benefits of mitochondrial training and elevate lactate levels. Consult your doctor.
16. Prioritize Quality of Life in Longevity
Focus on optimizing health and function in later years, not just extending lifespan, to ensure a high quality of life throughout longevity.
17. Question Endorsements for Trust
Be skeptical of product recommendations from individuals who are paid by the company, as this can compromise trust in their advocacy.
18. Advocate for Genuine Beliefs
Only advocate for products or ideas you are genuinely passionate about and believe in, as this authenticity builds trust and enthusiasm.
19. Be Aware of Statin Impact
Understand that statins can affect mitochondrial function and may increase the risk of developing diabetes, which is a long-term consideration when evaluating their use.
20. Support the Podcast for Content
Become a member to support the podcast if you value its content, gaining access to exclusive show notes, downloadable transcripts, AMA episodes, and deals on products Peter loves.
21. Avoid Carb Restriction for Elite Performance
Elite athletes should avoid acute carbohydrate restriction or ketogenic diets during competitive training and racing seasons, as the adaptation period is too long and can severely impair performance.
22. Consider Carb Restriction for Metabolic Health
For individuals not aiming for elite athletic performance, carbohydrate restriction can be a powerful tool to improve metabolic health, even if initial exercise performance is temporarily reduced.
23. Monitor Glucose During Zone 2
Track your glucose levels (e.g., with a continuous glucose monitor) during Zone 2 exercise, as a steady and consistent fall in glucose indicates effective non-insulin dependent glucose uptake and improved metabolic function.
24. Optimize Altitude Training with “Live High, Train Low”
For performance enhancement, aim to live at high altitude to increase oxygen-carrying capacity, but conduct high-intensity training at or near sea level to prevent deterioration of glycolytic capacity.
8 Key Quotes
So I always say that I admit it, I'm a truncated and frustrated professional athlete because I never got to the top. But that said, I learned a lot and it's been a school of life all my life.
Iñigo San Millán
We tend to believe that the immense majority of activity that we do is aerobic. We tend to believe that any hard effort is anaerobic and therefore the concept of anaerobic threshold. But actually, even what we call the anaerobic threshold is an aerobic activity.
Iñigo San Millán
Lactate is the most important, if not the most important fuel for the body.
Iñigo San Millán
This population is the population in the planet with the healthiest mitochondria. So that's what I call perfection. And that's what I try to bring to the table that in order to study other diseases where mitochondrial dysfunction is at the epicenter as well, we need to understand what perfection is in order to understand imperfection.
Iñigo San Millán
Watts are not watts at the metabolic level. It was very stressful for them and they could not keep it.
Iñigo San Millán
The heart rate is going to tell you a lot. This is one of the things also why I decided to try to develop a way to look at glycogen because I would see that in in maximal physiological states many athletes who were fatigued or restricting carbohydrates they had a very low maximum lactate levels very low maximum heart rate.
Iñigo San Millán
There's no population on earth who has as many carbohydrates and simple sugars as these athletes by a landslide.
Iñigo San Millán
If you can't do it for the rest of your life, you have to come back to the why am I doing this?
Iñigo San Millán
1 Protocols
Cool Down Protocol for Type 1 Diabetics
Iñigo San Millán- After high-intensity exercise that causes post-exercise hyperglycemia, perform a cool-down period.
- The sustained muscle contraction during the cool-down will translocate GLUT4 transporters to the muscle surface, facilitating non-insulin dependent glucose uptake.
- This helps bring down glucose levels without the need for additional insulin, preventing severe hypoglycemia later.